We review progress in the field of orthopaedic gene therapy since the concept of using gene transfer to address orthopaedic problems was initiated approximately 15 years ago. The original target, arthritis, has been the subject of two successful Phase I clinical trials, and additional human studies are pending in rheumatoid arthritis and osteoarthritis. The repair of damaged musculoskeletal tissues also has proved to be a fruitful area of research, and impressive enhancement of bone healing has been achieved in preclinical models. Rapid progress also is being made in the use of gene transfer to improve cartilage repair, ligament healing, and restoration of various additional tissues, including tendon and meniscus. Other applications include intervertebral disc degeneration, aseptic loosening, osteoporosis, genetic diseases, and orthopaedic tumors. Of these various orthopaedic targets of gene therapy, tissue repair is likely to make the earliest clinical impact because it can be achieved with existing technology. Tissue repair may become one of the earliest clinical successes for gene therapy as a whole. Orthopaedics promises to be a leading discipline for the use of human gene therapy.